We propose experiments in four areas dealing with eq. the formation of sickle hemoglobin (HbS) polymers and their effect on the red blood cell. (1) We shall continue our studies of the structure of HbS fibers which are primarily responsible for the pathological manifestations of sickle cell anemia. (2) Our past studies of the crystallization of fibers has provided important insights regarding the molecular rearrangements which accompany crystallization. We propose to extend these studies by (a) further characterization of the structure of crystallization intermediates (b) computer modeling of the fiber and crystallization intermediates using the crystal as the reference structure and (c) determination of the thermodynamic parameters driving crystallization. (3) Much of the existing knowledge about the polymerization of HbS has been obtained using static systems. We propose experiments in which polymerization of HbS will be studied in red cells subjected to rapidly changing deformation approaching what actually occurs in the vascualr circulation. (4) Finally we propose to investigate the structural changes in the red cell cytoskeleton which result in irreversible sickling.